Metastasis is the process by which a cancer cell locally invades the surrounding tissue, moves to the microvasculature of the blood and lymph system, migrates into distant tissues, and proliferates into a macroscopic secondary tumor. Cancer cell metastasis may occur at any stage of cancer development with more frequent incidence during last stage of cancers. All current strategies for the treatment of most kinds of cancer focus on removing the primary tumor directly (by surgery) or inhibiting the growth of the cancer (by chemotherapy and radiation). No specific strategy targets metastatic cancer cells. Therefore, the current survival rate for the metastatic cancer patients is extremely low even with optimal combination treatment via surgery, chemotherapy, and radiation. Comparatively, most cancers treated early have a high disease-free survival with optimal combination treatment because of the lower incidence rate of metastasis. For example, for stage 1 breast cancer patients, the 5-year survival rate is close 100%. For stage 2 and 3 patients, the 5-year survival rates are 93% and 72%, respectively. However, for metastatic breast cancer patients (stage 4), the 5 year survival rate is sharply reduced to 16-20%, even with currently optimal combination treatment.
Several kinds of cancer, such as breast, ovarian, gastric, prostate, lung and other cancers are associated with overexpression of human epidermal growth factor receptor 2 (HER2), which is a member of transmembrane receptor family that includes four HER receptors (HER1/EGFR, HER2, HER3 and HER4).1,2 HER receptors are essential to regulate cell proliferation and differentiation through interlinked signal transduction including Ras/Raf/MEK/MAPK and PI3K/Akt pathways.3 Ligand binding to the extracellular region induces the heterodimerization of HER receptors and the autophosphorylation of the HER cytoplasmic kinase domains (except for HER3 that has no kinase domain), which leads to the initiation of downstream signaling pathways.4 Inappropriate activation of HER receptors is associated with the initiation and development of many cancers.
As a key gene in cells, HER2 gene amplification and protein overexpression have been found in breast, ovarian, gastric, prostate, lung and other cancers.5, 6 The level of HER2 overexpression ranges widely between different cancer cells and different cancer stages. The HER2 overexpression level is much higher in advanced stage of cancers.7-9 For example, overexpression of HER2 protein or amplification of its gene occurs in 28% of human ovarian cancer cases at all stages of disease;7 but the rate reaches almost 100% in stage III and IV.8 Comparably, the overall rate of HER2 overexpression among all prostate cancer cases is 25%, but the overexpression rate in late stage of prostate tumors is 78%.9 Overexpression of HER2 protein is associated with more frequent recurrence, spread, and significantly poorer prognosis in these kinds of cancer. The greater expression of HER2 in cancer cells than normal tissue and the accessibility of its extracellular domain make HER2 an attractive target to develop strategies for therapeutic intervention. Recently, several monoclonal antibody-based therapeutics, such as trastuzumab (herceptin), pertuzumab, and MM-111, each of which targets the cancer cell surface antigen HER2, have been developed.4 Subsequently, an antibody-drug conjugate that combines the trastuzumab with a potent microtubule-disrupting agent, DM1 (T-DM1) also has been developed to increase the antibody's efficacy against HER2-positive cancers.10 However, a significant number of patients either do not respond or quickly relapse and exhibit resistance to existing HER2 therapies.
Small molecule drugs have been attractive agents for cancer treatment for many years because of their small size, oral availability, ability to cross membranes, and low cost. On the other hand, small molecules also have some limitations, such as low specificity and unacceptable toxicity. An antibody-drug conjugate, such as T-DM1 can specifically target to HER2 overexpressed cells. However, every antibody molecule can only delivery a few molecules of a small molecule drug. In addition, the covalent bonds between antibody and drugs limit the release of the small molecule drugs. Accordingly, there remains a need in the art for improved therapeutic compositions and therapeutic strategies for treating late stage, metastatic cancers. In particular, there remains a need for improved therapeutic compositions and methods for treating cancers, including metastatic cancers, associated with overexpression of HER2.